Abstract
The defective MEK/ERK signaling pathway and downstream hypomethylation pattern of lymphocytes are crucial for the pathogenesis of systemic lupus erythematosus (SLE). However, the role that the mesenchymal stem cells play in the MEK/ERK signaling pathway and DNA methylation of peripheral blood mononuclear cells (PBMC) from SLE patients remains unknown. In this study, we found that the MEK/ERK signaling pathway of PBMC from SLE patients was activated after the coculture with bone marrow-derived mesenchymal stem cells (BM-MSC) compared with that from the control group. In addition, the expression level of DNA methyltransferase 1 (DNMT1) increased while the levels of CD70, integrin, alpha L (ITGAL), selectin-l, and IL-13 were reduced in PBMC from SLE patients. However, no obvious effect of BM-MSC on PBMC from healthy controls was observed. These findings revealed that BM-MSC might downregulate the expression of methylation-sensitive genes and then suppress the autoactivated PBMC via the MEK/ERK signaling pathway. And it may be one of the mechanisms that BM-MSC ameliorated SLE.
Highlights
Characterized by the deposition of autoantibodies and immune complexes resulting in inflammation of multiple organs, systemic lupus erythematosus (SLE) is a refractory autoimmune disease involved in 2.2 to 23.1 out of 100000 per year globally [1]
The epigenetic regulation especially the DNA hypomethylation of T cells and the defective extracellular signal-regulated kinase (ERK) pathway has been extensively studied in SLE and brought great attention [4, 5]
Since we found that Bone marrow mesenchymal stem cells (BM-MSC) upregulated the expression of DNA methyltransferase 1 (DNMT1), we assumed that BM-MSC could alter the expression of methylationsensitive genes of peripheral blood mononuclear cells (PBMC) from SLE patients
Summary
Characterized by the deposition of autoantibodies and immune complexes resulting in inflammation of multiple organs, systemic lupus erythematosus (SLE) is a refractory autoimmune disease involved in 2.2 to 23.1 out of 100000 per year globally [1]. The epigenetics including DNA methylation, histone modification, and noncoding RNA has been considered extremely important in the pathogenesis of SLE in recent decades [3]. The epigenetic regulation especially the DNA hypomethylation of T cells and the defective extracellular signal-regulated kinase (ERK) pathway has been extensively studied in SLE and brought great attention [4, 5]. Activating the ERK signaling pathway and restoring the hypermethylation of T cells may be a potential treatment for lupus. The immunomodulatory function of BM-MSC has been well studied in various diseases. The transplantation of BM-MSC has been regarded as a new therapy for inflammatory diseases including lupus either alone or in combination with other drugs [7]. The transplantation of MSC has been proven to be an efficient and safe
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